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Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography.

ABSTRACT: SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors are currently under clinical investigation, whereas there are no reports to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to identify X-ray cocrystal structures of five diverse fragment hits bound to SOS2.

SUBMITTER: Smith CR

PROVIDER: S-EPMC10788894 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography.

Smith Christopher R CR Chen Dan D Christensen James G JG Coulombe René R Féthière James J Gunn Robin J RJ Hollander Johan J Jones Benjamin B Ketcham John M JM Khare Shilpi S Kuehler Jon J Lawson J David JD Marx Matthew A MA Olson Peter P Pearson Kelly E KE Ren Cynthia C Tsagris Denise D Ulaganathan Thirumalaiselvi T Van't Veer Inge I Wang Xiaolun X Ivetac Anthony A

Journal of medicinal chemistry 20231229 1

SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors are currently under clinical investigation, whereas there are no reports to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to iden ...[more]

PMID: 38156904

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